Amyotrophic lateral sclerosis (ALS), which affects about 35,000 Americans, is arguably the most pernicious of the adult-onset neurodegenerative diseases because of its relatively early onset and rapid progression between diagnosis and death. There is no effective treatment for ALS and no progress towards this goal is expected from the private sector, since confirmed "druggable targets" have not emerged and the market is too small to justify an intense research effort to identify such targets. This proposal outlines a first step towards a new class of ALS therapeutics. Aggregation of SOD1 may be pathogenic in familial ALS. Previously, we have demonstrated that aggregation of SOD is coupled to the dissociation of dimeric SOD into monomers. We believe that stabilization of the dimeric form of SOD by small drug-like molecules may be a viable strategy to develop a new class of ALS therapeutics. We propose to screen a library of 100,000 drug-like molecules for (1) Molecules that promote dimer stability in SOD (2) Prevent aggregation of SOD. In order to do this, we will develop fluorescence-based assays that will probe both dimerization and aggregation of SOD. The set of molecules identified from the screen will be subjected to secondary assays which will rely on the direct ability of these compounds to block aggregation. Our long term goal is to use a combination of screening and medicinal chemistry to develop compounds that can be tested in a mice model for ALS. Our ultimate goal is to identify candidates that justify filing for IND status.